Sorting nexin 1 loss results in increased oxidative stress and hypertension

Jian Yang; Laureano D. Asico; Amber L. Beitelshees; Jun B. Feranil; Xiaoyan Wang; John E. Jones; Ines Armando; Santiago G. Cuevas; Gary L. Schwartz; John G. Gums; Arlene B. Chapman; Stephen T. Turner; Eric Boerwinkle; Rhonda M. Cooper-DeHoff; Julie A. Johnson; Robin A. Felder; Edward J. Weinman; Chunyu Zeng; Pedro A. Jose; Van Anthony M. Villar

doi:10.1096/fj.201902448R

Sorting nexin 1 loss results in increased oxidative stress and hypertension

Jian Yang, Laureano D. Asico, Amber L. Beitelshees, Jun B. Feranil, Xiaoyan Wang, John E. Jones, Ines Armando, Santiago G. Cuevas, Gary L. Schwartz, John G. Gums, Arlene B. Chapman, Stephen T. Turner, Eric Boerwinkle, Rhonda M. Cooper-DeHoff, Julie A. Johnson, Robin A. Felder, Edward J. Weinman, Chunyu Zeng, Pedro A. Jose, Van Anthony M. Villar

Nephrology and Hypertension

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D₅ receptor (D₅R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1^−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT₁R), NADPH oxidase (NOX) subunits, D₅R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1^-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D₅R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D₅R agonist-induced increase in cAMP production and decrease in Na⁺ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Original language	English (US)
Pages (from-to)	7941-7957
Number of pages	17
Journal	FASEB Journal
Volume	34
Issue number	6
DOIs	https://doi.org/10.1096/fj.201902448R
State	Published - Jun 1 2020

Keywords

dopamine D receptor
hypertension
oxidative stress
renal proximal tubule cells
sorting nexin 1

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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10.1096/fj.201902448R

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Yang, J., Asico, L. D., Beitelshees, A. L., Feranil, J. B., Wang, X., Jones, J. E., Armando, I., Cuevas, S. G., Schwartz, G. L., Gums, J. G., Chapman, A. B., Turner, S. T., Boerwinkle, E., Cooper-DeHoff, R. M., Johnson, J. A., Felder, R. A., Weinman, E. J., Zeng, C., Jose, P. A., & Villar, V. A. M. (2020). Sorting nexin 1 loss results in increased oxidative stress and hypertension. FASEB Journal, 34(6), 7941-7957. https://doi.org/10.1096/fj.201902448R

Yang, J, Asico, LD, Beitelshees, AL, Feranil, JB, Wang, X, Jones, JE, Armando, I, Cuevas, SG, Schwartz, GL, Gums, JG, Chapman, AB, Turner, ST, Boerwinkle, E, Cooper-DeHoff, RM, Johnson, JA, Felder, RA, Weinman, EJ, Zeng, C, Jose, PA & Villar, VAM 2020, 'Sorting nexin 1 loss results in increased oxidative stress and hypertension', FASEB Journal, vol. 34, no. 6, pp. 7941-7957. https://doi.org/10.1096/fj.201902448R

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title = "Sorting nexin 1 loss results in increased oxidative stress and hypertension",

abstract = "Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.",

keywords = "dopamine D receptor, hypertension, oxidative stress, renal proximal tubule cells, sorting nexin 1",

author = "Jian Yang and Asico, {Laureano D.} and Beitelshees, {Amber L.} and Feranil, {Jun B.} and Xiaoyan Wang and Jones, {John E.} and Ines Armando and Cuevas, {Santiago G.} and Schwartz, {Gary L.} and Gums, {John G.} and Chapman, {Arlene B.} and Turner, {Stephen T.} and Eric Boerwinkle and Cooper-DeHoff, {Rhonda M.} and Johnson, {Julie A.} and Felder, {Robin A.} and Weinman, {Edward J.} and Chunyu Zeng and Jose, {Pedro A.} and Villar, {Van Anthony M.}",

note = "Publisher Copyright: {\textcopyright} 2020 Federation of American Societies for Experimental Biology",

year = "2020",

month = jun,

day = "1",

doi = "10.1096/fj.201902448R",

language = "English (US)",

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T1 - Sorting nexin 1 loss results in increased oxidative stress and hypertension

AU - Yang, Jian

AU - Asico, Laureano D.

AU - Beitelshees, Amber L.

AU - Feranil, Jun B.

AU - Wang, Xiaoyan

AU - Jones, John E.

AU - Armando, Ines

AU - Cuevas, Santiago G.

AU - Schwartz, Gary L.

AU - Gums, John G.

AU - Chapman, Arlene B.

AU - Turner, Stephen T.

AU - Boerwinkle, Eric

AU - Cooper-DeHoff, Rhonda M.

AU - Johnson, Julie A.

AU - Felder, Robin A.

AU - Weinman, Edward J.

AU - Zeng, Chunyu

AU - Jose, Pedro A.

AU - Villar, Van Anthony M.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

AB - Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

KW - dopamine D receptor

KW - hypertension

KW - oxidative stress

KW - renal proximal tubule cells

KW - sorting nexin 1

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SN - 0892-6638

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EP - 7957

JO - FASEB Journal

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Sorting nexin 1 loss results in increased oxidative stress and hypertension

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